Our research goal has been primarily directed toward understanding the molecular basis for HIV-1 infection of non-dividing cells. Lentiviruses, such as HIV-1, replicate independently of cell cycle progression of target cells and this property is unusual among retroviruses, which require cell division for efficient replication. This unique ability of HIV-1 to replicate in non-dividing cells allows the virus to infect resting CD4+ T cells and terminally differentiated macrophages, the two cell types believed to play critical roles in transmission, persistence and pathogenesis of HIV-1. We previously determined that the capsid protein of the virus is the dominant viral factor responsible for infection of non-dividing cells. Current work in our laboratory focuses on understanding how the capsid protein mediates the early steps of the viral life cycle to promote HIV-1 infection of non-dividing cells.

HIV-1 exploits a variety of cellular pathways to establish productive infection of target cells. Recent genome-wide screens have uncovered a large number of cellular factors that affect HIV-1 replication. Among those are positive factors potentially involved in the early steps of the viral life cycle such as TNPO3, which appears to be regulated by the capsid protein of HIV-1. Currently, our group is interested in learning how capsid utilizes cellular molecules to facilitate uncoating, nuclear transport and integration in non-dividing cells. Ultimately, we hope to understand how the difference in cellular pathways utilized by retroviruses can result in diverse disease outcomes from cancer to AIDS.

Despite the presence of cellular factors that positively regulate the viral life cycle, the host environment is not always friendly to viral replication. After repeated times of arms-races with ancient viruses, host cells are equipped with cellular factors that restrict the spread of retroviruses. In order to efficiently replicate in humans, HIV-1 has evolved mechanisms to evade or counteract host restriction factors that can target incoming viral capsid. We are currently working to delineate the molecular details and mechanisms of HIV-1 evasion from the capsid-dependent defense system. Our hypothesis is that this evasion is indispensable not only for HIV-1 adaptation after cross-species transmission but also for retention of its ability to infect non-dividing cells.

Our primary goal is to elucidate molecular mechanism that enables HIV-1 to infect non-dividing cells, such as resting CD4+ T cells and macrophages. This property, which is unique to HIV-1 and related lentiviruses but not other retroviruses, is central to HIV transmission, persistence and pathogenesis. Recent work points to viral capsid protein as the long sought determinant that provides HIV-1 with the ability to establish productive infection in non-dividing cells. We are currently studying cellular factors that regulate capsid-mediated early events to learn how capsid promotes HIV-1 infection of non-dividing cells. In order to efficiently infect host cells, HIV-1 has to achieve some balance between two opposing types of cellular factors that either promote or thwart viral replication. We seek to identify a way to tip this balance in favor of cellular factors that attenuate HIV-1, which may be a useful knowledge for developing new therapeutic strategies targeting HIV-1 capsid.

Yamashita M., Picchio G, Veronesi R, Ohkura S, Bare P and Hayami M. 1998. HTLV-Is in Argentina are phylogenetically similar to those of other South American countries, but different from HTLV-Is in Africa. J Med Virol 55:152-160.

Yamashita M, Picchio G, Veronesi R, Ohkura S, Bare P and Hayami M. 1998. HTLV-Is in Argentina are phylogenetically similar to those of other South American countries, but different from HTLV-Is in Africa. J Med Virol 55:152-160. [view]